Communications
dride (1 mmol), the alkaloid (1.1 equiv of quinine or quinidine;
Kaupp, J. Schmeyers, J. Boy, J. Prakt. Chem. 2000, 342, 269 – 280;
d) G. Kaupp, Top. Curr. Chem. 2005, 254, 95 – 183.
0.1 equiv of hydroquinone anthraquinone-1,4-diyl diether
((DHQ)2AQN), and the alcohol (1.0 equiv). The vessel was closed,
and the milling was started (milling time: 24–36 h at 250 rpm;
sequential intervals of 25-min milling followed by a 5-min pause).[9]
After completion of the reaction, the mixture was carefully washed
with 2n HCl and transferred into a separation funnel using EtOAc.
The mixture was extracted three times with EtOAc, and the organic
fractions were combined and dried (MgSO4). The solvent was
evaporated and if required, the product was purified by flash
chromatography.
[7] For some recent reviews on enantioselective organocatalysis,
see: a) A. Berkessel, H. Gröger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, 2005; b) J. Seayad, B. List, Org. Biomol.
Chem. 2005, 3, 719 – 724; c) P. M. Pihko, Angew. Chem. 2006,
118, 558 – 561; Angew. Chem. Int. Ed. 2006, 45, 544 – 547; d) B.
List, Chem. Commun. 2006, 819 – 824.
[8] a) C. Bolm, A. Gerlach, C. L. Dinter, Synlett 1999, 195 – 196;
b) C. Bolm, I. Schiffers, C. L. Dinter, A. Gerlach, J. Org. Chem.
2000, 65, 6984 – 6991; c) C. Bolm, I. Atodiresei, I. Schiffers, Org.
Synth. 2005, 82, 120 – 125; d) see also: Y. Chen, P. McDaid, L.
Deng, Chem. Rev. 2003, 103, 2965 – 2984.
[9] Decreasing the rotational speed or trying to perform the reaction
in a round-bottom flask led to lower substrate conversions as a
result of inefficient mixing. Ball milling without pause resulted in
a product with a lower ee value, presumably as a result of the
observed temperature increase. Use of more than one equivalent
of quinidine had no positive effect on the enantioselectivity. Low
substrate conversions were observed when the alkaloid amount
was reduced to 10 mol% or (DHQ)2AQN was applied as the
catalyst (compare protocols reported by Deng and co-workers in
Ref. [8d]).
General procedure for the proline-catalyzed solvent-free aldol
reaction: A reaction vessel was charged with aldehyde 5 (2.0 mmol,
1.0 equiv), ketone 4 (2.2 mmol, 1.1 equiv), and (S)-proline (23 mg,
0.2mmol, 0.1 equiv). Stirring was either started in a grinding bowl
using the ball mill with a rotation speed of 250–400 rpm (Table 1,
method A), or in a round-bottomed flask using a conventional
magnetic stirring bar (method B). After an appropriate reaction time,
the crude product was washed off the reaction vessel with Et2O (4
40 mL), and the combined organic fractions were filtered and
concentrated in vacuo. The diastereoselectivity of the reaction was
determined by 1H NMR spectroscopic analysis of the crude product.
Purification by flash chromatography on silica gel (pentane/EtOAc,
100:0!80:20) afforded the pure aldol product 6a–h in the yields and
enantioselectivities reported in Table 1. The identity and purity of the
[10] Reactions between other meso anhydrides and alcohols led to
analogous results; details of this study will be reported in due
course.
1
products were confirmed by H and 13C NMR spectroscopic analysis
(see Supporting Information for full details).
[11] For some selected examples, see: a) B. List, R. A. Lerner, C. F.
Barbas III, J. Am. Chem. Soc. 2000, 122, 2395 – 2396; b) P. M.
Pihko, K. M. Laurikainen, A. Usano, A. I. Nyberg, J. A. Kaavi,
Tetrahedron 2006, 62, 317 – 328; c) review: B. List, Acc. Chem.
Res. 2004, 37, 548 – 557.
Received: July 14, 2006
Published online: September 26, 2006
[12] For organocatalytic aldol reactions in water, see: a) Y. Hayashi,
T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji,
Angew. Chem. 2006, 118, 972– 975; Angew. Chem. Int. Ed. 2006,
45, 958 – 961; b) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K.
Takabe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
734 – 735; c) for a general concept article, see: M. C. Pirrung,
Chem. Eur. J. 2006, 12, 1312– 1317, and references therein.
[13] Isolated examples of solvent-free organocatalytic aldol reactions
can be found in references [11] and [12]. However, to the best of
our knowledge, such approach has never been the focus of an
intense study. It should also be noted that in these cases an excess
of liquid ketone (ꢁ 5 equiv) appears essential for achieving both
high yields and stereoselectivities.
[14] For interesting phenomena in this organocatalysis based on the
solid–liquid phase behavior of proline, see: a) M. Klussmann, H.
Iwamura, S. P. Mathew, D. H. Wells, Jr., U. Pandya, A. Arm-
strong, D. G. Blackmond, Nature 2006, 441, 621 – 623; b) Y.
Hayashi, M. Matsuzawa, J. Yamaguchi, S. Yonehara, Y. Matsu-
moto, M. Shoji, D. Hashizume, H. Koshino, Angew. Chem. 2006,
118, 4709 – 4713; Angew. Chem. Int. Ed. 2006, 45, 4593 – 4597.
[15] This rate enhancement might also be due to the elevated
temperature in the ball-mill experiment; for proline-catalyzed
Mannich reactions, the significant temperature tolerance has
recently been established: B. Rodrꢀguez, C. Bolm, J. Org. Chem.
2006, 71, 2888 – 2891.
Keywords: aldol reaction · anhydrides · ball mill ·
organocatalysis · solvent-free reactions
.
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